Non-bioconvertible c3-substituted pregnenolone derivatives for use in the treatment of substance use disorders

ABSTRACT

The present invention relates to the use of non-bioconvertible C3-substituted pregnenolone derivatives of formula (I), with no significant affinity for hormonal receptors or receptors of the central nervous system, in the treatment of substance use disorders, and in particular of alcohol use disorder.

TECHNICAL FIELD OF THE INVENTION

The present invention is in the field of treatment of substance usedisorders. It relates to the use of particular derivatives ofpregnenolone, which are blocked in C₃ position and cannot metabolize invivo into pregnenolone derivatives and which do not have significantaffinity for steroid hormonal receptors and for all tested classicalmain receptors and receptors of neurotransmitters of the central nervoussystem, for the treatment of substance use disorders.

BACKGROUND ART

Substance use disorders (SUDs) are a group of complex behavioral andchronically relapsing disorders characterized by the presence of (1)loss of control, (2) social impairment, (3) risky use of the substance,and/or (4) pharmacological tolerance and withdrawal. SUDs lead tosignificant health and public order problems, and treatments of thesedisorders are highly desirable. At the biological level, SUDs arecharacterized by alteration of several neurological signaling pathways,and various treatments aiming to restore normal signaling have beenproposed. In particular:

-   -   SUDs are known to alter γ-aminobutyric acid (GABA)        neurotransmission, and negative allosteric modulators of the        GABA_(A) receptor, and GABA_(B) direct agonists such as baclofen        or GABA_(B) positive allosteric modulators have been proposed        for the treatment of SUDs (Addolorato G et al.        Neuropsychopharmacology. 2012 January; 37(1):163-77). Gabapentin        also increases GABA neurotransmission, which may also explain        its effect on SUDs. Topiramate, a glutamatergic compound, also        increases GABA_(A)-facilitated neuronal activity, which may also        explain its effect on SUDs (Addolorato G et al.        Neuropsychopharmacology. 2012 January; 37(1):163-77). In this        respect, ganaxolone, a synthetic GABAergic steroid, and        pregnenolone, a precursor of all GABAergic neuroactive steroids        in vivo, have also been shown to reduce operant ethanol        self-administration in alcohol-preferring P rats (Besheer J, et        al. Alcohol Clin Exp Res. 2010 December; 34(12):2044-52).    -   SUDs are also known to alter cannabinoid CB1 receptor signaling,        and CB1 receptor antagonists have been proposed for treatment of        SUDs (Le Foil B, Goldberg S R. Cannabinoid CB1 receptor        antagonists as promising new medications for drug dependence. J        Pharmacol Exp Ther. 2005 March; 312(3):875-83; WO2012160006A1).    -   SUDs are also known to alter glutamatergic transmission and        glutamatergic compounds (acamprosate, N-acetylcysteine,        D-cycloserine, gabapentin, lamotrigine, memantine, modafinil,        and topiramate) have been proposed for treatment of SUDs (Olive        M F et al. Pharmacol Biochem Behav. 2012 February;        100(4):801-10).    -   SUDs are also known to alter kappa-opioid receptors (KORs) and        their endogenous ligands dynorphins (DYNs), and compounds        targeting this signaling pathway have been proposed for        treatment of SUDs (Walker B M et al. Alcohol. 2012 June;        46(4):359-70).    -   SUDs are also known to alter Corticotropin-Releasing Factor        (CRF) receptor signaling, and CRF receptor (CRFR) antagonists        have been proposed for treatment of SUDs (Lowery E G, Thiele        T E. CNS Neurol Disord Drug Targets. 2010 March; 9(1):77-86).    -   Voltage- and calcium-gated ion channels are critical modulators        of neuronal excitability, and modulators of ion channel function        have also been proposed for treatment of SUDs. In particular,        L-type voltage-dependent calcium channel (LVDCC) blockers        (including the 1 ,4-dihydropyridine (DHP) derivatives        israpidine, nimodipine, and nifedipine, and the phenylalkylamine        verapamil) have been proposed for treatment of withdrawal        symptoms in human addicts. N- and T-type calcium channels (NVDCC        and TVDCC) blockers have also been proposed (Addolorato G et al.        Neuropsychopharmacology. 2012 January; 37(1):163-77).    -   Lamotrigine, which inhibits sodium channel activity, has also        been proposed for treatment of SUDs (Addolorato G et al.        Neuropsychopharmacology. 2012 January; 37(1):163-77).

However, none of the above treatments is completely satisfactory andfurther treatment opportunities are needed. In particular, clinicalresults have not systematically confirmed preclinical results, oradverse effects limit the use of some compounds. For instance, CB1receptor antagonist rimonabant is known to induce adverse effects suchas severe depression and suicidal thoughts, which limits its potentialuse.

In addition, as illustrated above, many neurological signaling pathwaysare altered in SUDs, and many compounds modulating one of these pathwaysalso modulate other signaling pathways, either directly (see the aboveexamples of gabapentin and topiramate) or via metabolites generated invivo having different activities. This makes understanding of crucialsignaling pathways and of optimal active compounds extremelycomplicated.

3β-methoxy-pregna-5-ene-20-one (also referred to as3β-methoxy-pregnenolone or 3β-methoxy-PREG) is a synthetic derivative ofpregnenolone (3β-hydroxypregn-5-en-20-one), the natural precursor ofsteroid hormones, and in particular of neurosteroids. The 3β-methoxyfunction of 3β-methoxy-PREG prevents its conversion to its neuroactivemetabolites.

It has been shown that 3β-methoxy-PREG is highly specific for itsreceptor MAP2. In particular, 3β-methoxy-PREG has no activity onprogesterone receptor (see Example 11 of US20140228336A2 and Example 1of the present description), and has also no androgenic, estrogenic,glucocorticoid and mineral corticoid activity (see Example 13 ofUS20140228336A2 and Example 2 of the present description). Moreover,3β-methoxy-PREG has also been shown to have no significant affinity formany other receptors of the Central Nervous System (CNS), includingmuscarinic (cholinergic), histaminergic, noradrenergic, serotoninergic,dopaminergic, GABA, NMDA, cannabinoid, and oppioid receptors (see Table4 of US20140228336A2 and Example 3 of the present description). Thiscompound is thus devoid of significant activity for most of signalingreceptors known to be altered in SUDs, and for which modulation has beenproposed as therapeutic strategy for treating SUDs.

SUMMARY OF THE INVENTION

However, in the context of the present invention, the inventorssurprisingly found that 3β-methoxy-PREG is able to significantly andspecifically reduce excessive alcohol drinking in a model of long timealcohol dependent rats, while showing no adverse effect.

The present invention thus relates to a compound of formula (I):

wherein:

each of

independently represents a single or a double bond;

R₁ represents a C₁-C₄ alkyl;

R₂ represents —CO—; —CH(OH)— or —CH(O—COCH₃)—; and

R₃ represents H or CHCl₂ and R₄ represents H or CH₃, or R₃ and R₄together represent

or a pharmaceutically acceptable salt thereof,

for use in the treatment or relapse prevention of a substance usedisorder.

The present invention also relates to a method for treating orpreventing relapse of a substance use disorder in a subject in needthereof, comprising administering to said patient a therapeuticallyefficient amount of a compound of formula (I):

wherein:

each of

independently represents a single or a double bond;

R₁ represents a C₁-C₄ alkyl;

R₂ represents —CO—; —CH(OH)— or —CH(O—COCH₃)—; and

R₃ represents H or CHCl₂ and R₄ represents H or CH₃, or R₃ and R₄together represent

or a pharmaceutically acceptable salt thereof.

DESCRIPTION OF THE FIGURES

FIG. 1. Test of progesterone receptor agonist activity.

FIG. 2. Test of progesterone receptor antagonist activity.

FIG. 3. Effect of chronic MAP4343 (10 mg/kg) on alcoholself-administration in dependent (vapor) and non-dependent (air)animals. Values represent the mean (±S.E.M) number of alcohol reinforcedresponses. *: significant (p<0.05) difference between vapor vehicle andvapor MAP4343.

FIG. 4. White blood cells (WBC) counts (×10³ cells/μL) in dependent(Vapor) and non-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

FIG. 5. Red blood cells (RBC) counts (×10⁶ cells/μL) in dependent(Vapor) and non-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

FIG. 6. Platelets counts (×10³ cells/μL) in dependent (Vapor) andnon-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

FIG. 7. Neutrophils counts in dependent (Vapor) and non-dependent (Air)rats before (pre-treatment) and after (post-treatment) treatment withvehicle (Veh) or MAP4343.

FIG. 8. T4 level (μg/dL) in dependent (Vapor) and non-dependent (Air)rats before (pre-treatment) and after (post-treatment) treatment withvehicle (Veh) or MAP4343.

FIG. 9. T3 level (ng/dL) in dependent (Vapor) and non-dependent (Air)rats before (pre-treatment) and after (post-treatment) treatment withvehicle (Veh) or MAP4343.

FIG. 10. Blood urea nitrogen level (mg/dL) in dependent (Vapor) andnon-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

FIG. 11. Creatinine level (mg/dL) in dependent (Vapor) and non-dependent(Air) rats before (pre-treatment) and after (post-treatment) treatmentwith vehicle (Veh) or MAP4343.

FIG. 12. Cholesterol level (mg/dL) in dependent (Vapor) andnon-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

FIG. 13. Protein level (g/dL) in dependent (Vapor) and non-dependent(Air) rats before (pre-treatment) and after (post-treatment) treatmentwith vehicle (Veh) or MAP4343.

FIG. 14. Albumin level (g/dL) in dependent (Vapor) and non-dependent(Air) rats before (pre-treatment) and after (post-treatment) treatmentwith vehicle (Veh) or MAP4343.

FIG. 15. Alpha1-globulin level (g/dL) in dependent (Vapor) andnon-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

FIG. 16. Alpha2-globulin level (g/dL) in dependent (Vapor) andnon-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

FIG. 17. beta-globulin level (g/dL) in dependent (Vapor) andnon-dependent (Air) rats before (pre-treatment) and after(post-treatment) treatment with vehicle (Veh) or MAP4343.

DETAILED DESCRIPTION OF THE INVENTION Definitions

A “substance use disorder” or “SUD” is defined according to criteria ofthe 5th edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-5). In this respect, SUD is diagnosed if at least two ofthe following criteria are met within a 12-month period:

-   -   Impaired control criteria (1 to 4):        -   1. Substance is often taken in larger amounts or over a            longer period than was intended.        -   2. There is a persistent desire or unsuccessful efforts to            cut down or control substance use.        -   3. A great deal of time is spent in activities necessary to            obtain substance, use substance, or recover from its            effects.        -   4. Craving, or a strong desire or urge to use substance.    -   Social impairment criteria (5 to 7):        -   5. Recurrent substance use resulting in a failure to fulfill            major role obligations at work, school, or home.        -   6. Continued substance use despite having persistent or            recurrent social or interpersonal problems caused or            exacerbated by the effects of substance.        -   7. Important social, occupational, or recreational            activities are given up or reduced because of substance use.    -   Risky use of substance criteria (8 and 9):        -   8. Recurrent substance use in situations in which it is            physically hazardous.        -   9. Substance use is continued despite knowledge of having a            persistent or recurrent physical or psychological problem            that is likely to have been caused or exacerbated by            substance.    -   Pharmacological criteria (10 and 11):        -   10. Tolerance, as defined by either of the following:            -   a) A need for markedly increased amounts of substance to                achieve intoxication or desired effect            -   b) A markedly diminished effect with continued use of                the same amount of substance.        -   11. Withdrawal, as manifested by either of the following:            -   a) The characteristic withdrawal syndrome for substance            -   b) substance (or a closely related substance) is taken                to relieve or avoid withdrawal symptoms.

SUD is considered as mild if 2 or 3 of the above criteria are met withinsaid period of 12 months, moderate if 4 to 5 of the above criteria aremet within said period of 12 months, and severe if 6 or more of theabove criteria are met within said period of 12 months.

Substances that may lead to SUDs include: alcohol; cannabis;hallucinogens (including phencyclidine, ketamine, and LSD); opioids(including codeine, fentanyl, heroin, morphine, opium, methadone,oxycodone, and hydrocodone); sedative, hypnotic or anxiolyticmedications (including barbiturates and benzodiazepines); stimulants(including nicotine, amphetamine, and methylphenidate); and inhalants(such as glue, shoe polish, toluene, spray paints, gasoline, and lighterfluid).

In particular, for “alcohol use disorder” or “AUD”, AUD is diagnosed ifat least two of the following criteria are met within a 12-month period:

-   -   Impaired control criteria (1 to 4):        -   1. Alcohol is often taken in larger amounts or over a longer            period than was intended.        -   2. There is a persistent desire or unsuccessful efforts to            cut down or control alcohol use.        -   3. A great deal of time is spent in activities necessary to            obtain alcohol, use alcohol, or recover from its effects.        -   4. Craving, or a strong desire or urge to use alcohol.    -   Social impairment criteria (5 to 7):        -   5. Recurrent alcohol use resulting in a failure to fulfill            major role obligations at work, school, or home.        -   6. Continued alcohol use despite having persistent or            recurrent social or interpersonal problems caused or            exacerbated by the effects of alcohol.        -   7. Important social, occupational, or recreational            activities are given up or reduced because of alcohol use.    -   Risky use of alcohol criteria (8 and 9):        -   8. Recurrent alcohol use in situations in which it is            physically hazardous.        -   9. Alcohol use is continued despite knowledge of having a            persistent or recurrent physical or psychological problem            that is likely to have been caused or exacerbated by            alcohol.    -   Pharmacological criteria (10 and 11):        -   10. Tolerance, as defined by either of the following:            -   a) A need for markedly increased amounts of alcohol to                achieve intoxication or desired effect            -   b) A markedly diminished effect with continued use of                the same amount of alcohol.        -   11. Withdrawal, as manifested by either of the following:            -   a) The characteristic withdrawal syndrome for alcohol            -   b) Alcohol (or a closely related substance, such as a                benzodiazepine) is taken to relieve or avoid withdrawal                symptoms.

AUD is considered as mild if 2 or 3 of the above criteria are met withinsaid period of 12 months, moderate if 4 to 5 of the above criteria aremet within said period of 12 months, and severe if 6 or more of theabove criteria are met within said period of 12 months.

By “treatment” or “treating” is meant an improvement of clinical orbiological criteria in the subject. For instance, “treatment” or“treating” may correspond to a decrease in the number or intensity ofcriteria 1 to 11 defined above for substance use disorders. By“prevention” or “preventing” is meant the fact to prevent or delay theonset or reduce the intensity of clinical or biological criteriaassociated to the substance use disorder. More precisely, in the contextof “relapse prevention”, it is referred to the fact to the fact toprevent or delay substance use disorder relapse or to reduce theintensity of substance use disorder relapse. In the case of reducing theintensity of substance use disorder relapse, the reduction maycorrespond to the presence of a decreased number of the 11 above definedcriteria or to the presence of the same criteria as before but withreduced intensity.

A “therapeutically effective amount” corresponds to an amount necessaryto impart therapeutic or a preventive benefit to a subject, as definedabove.

For the purpose of the present invention, the term “C₁-C₄ alkyl” isintended to mean any linear or branched saturated hydrocarbon radicalhaving from one to four carbon atoms. Examples of C₁-C₄ alkyl groupsinclude a methyl (CH₃) or an ethyl (C₂H₆) group. “Pharmaceuticallyacceptable salts” refer to salts that are suitable for use in contactwith the tissues of humans and animals without undue toxicity,irritation, allergic response, and the like. Examples of suitable saltsinclude salts of alkali metals such as potassium, sodium, lithium, saltsof alkaline earth metals such as calcium, magnesium and acid additionsalts with inorganic and organic acids are, but are not limited to,hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid,sulphuric acid, citric acid, formic acid, fumaric acid, maleic acid,lactic acid, malic acid, acetic acid, succinic acid, hemisuccinic acid,tartaric acid, methane-sulfonic acid, p-toluenesulphonic acid, trifluoroacetic acid and the like.

Compounds for Use in the Treatment of SUDs

The present invention relates to a compound of formula (I):

wherein:

each of

independently represents a single or a double bond;

R₁ represents a C₁-C₄ alkyl;

R₂ represents —CO—; —CH(OH)— or —CH(O—COCH₃)—; and

R₃ represents H or CHCl₂ and R₄ represents H or CH₃, or R₃ and R₄together represent

or a pharmaceutically acceptable salt thereof,

for use in the treatment or relapse prevention of a substance usedisorder.

The present invention also relates to a method for treating orpreventing relapse of a substance use disorder in a subject in needthereof, comprising administering to said patient a therapeuticallyefficient amount of a compound of formula (I):

wherein:

each of

independently represents a single or a double bond;

R₁ represents a C₁-C₄ alkyl;

R₂ represents —CO—; —CH(OH)— or —CH(O—COCH₃)—; and

R₃ represents H or CHCl₂ and R₄ represents H or CH₃, or R₃ and R₄together represent

or a pharmaceutically acceptable salt thereof.

Stereochemistry may be important for activity of the compound of formula(I). As a result, in the above therapeutic uses, the compound ispreferably of a compound of formula (Ib), and even more preferably acompound of formula (Ic):

wherein:

each of

independently represents a single or a double bond;

R₁ represents a C₁-C₄ alkyl;

R₂ represents —CO—; —CH(OH)— or —CH(O—COCH₃)—; and

R₃ represents H or CHCl₂ and R₄ represents H or CH₃, or R₃ and R₄together represent

Preferably, in the above therapeutic uses, the compound is of formula(II):

wherein:

represents a single or a double bond;

R₁ represents a C₁-C₄ alkyl;

R₂ represents —CO— or —CH(OH)—; and

R₃ represents H or CHCl₂.

In formula (II) also, stereochemistry may be important for activity ofthe compound. As a result, in the above therapeutic uses, the compoundis preferably of a compound of formula (IIb), and even more preferably acompound of formula (IIc):

wherein

, R₁, R₂, and R₃ are as defined above for formula (II).

In a preferred embodiment of anyone of formulas (I), (Ib), (Ic), (II),(IIb), and (IIc) above, R₁ is CH₃.

Alternatively or in combination, in anyone of formulas (I), (Ib), (Ic),(II), (IIb), and (IIc) above,

is preferably a double bond.

Alternatively or in combination, in anyone of formulas (I), (Ib), (Ic),(II), (IIb), and (IIc) above, R₂ is preferably —CO—.

Alternatively or in combination, in anyone of formulas (I), (Ib), (Ic),(II), (IIb), and (IIc) above, R₃ represents H.

It should be noted that any preferred bond/group for any of thesubstituents may be combined with any other preferred bond/group foranother of the substituents.

Preferred compounds for the above therapeutic uses are those describedin Table 1 below, or any pharmaceutically acceptable salt thereof:

TABLE 1 Preferred compounds for use in the invention Compound Formula3-methoxy-pregna-5- ene-20-one

3-methoxy-pregna-5- ene-20-ol

3-methoxy-pregna-5- ene-20-one-17- dichloromethyl

3-methoxy-5-pregnane- 20-one

3-methoxy-5-pregnane- 20-ol

A particularly preferred compound is 3-methoxy-pregna-5-ene-20-one(3-methoxy-PREG), of formula:

For compounds also, stereochemistry may be important for activity of thecompound. As a result, in the above therapeutic uses, the compound ispreferably selected from those described in Table 2 below, or anypharmaceutically acceptable salt thereof:

TABLE 2 Preferred compounds for use in the invention Compound Formula3β-methoxy-pregna-5-ene-20- one

3β-methoxy-pregna-5-ene-20β- ol

3β-methoxy-pregna-5-ene-20α- ol

3β-methoxy-pregna-5-ene-20- one-17α-dichloromethyl

3β-methoxy-5α-pregnane-20- one

3β-methoxy-5α-pregnane-20β-ol

3β-methoxy-5α-pregnane-20α-ol

A particularly preferred compound is 3β-methoxy-pregna-5-ene-20-one(3β-methoxy-PREG), of formula:

Preparation of the Compounds

The above defined compounds or pharmaceutically acceptable salts thereofmay be prepared easily using conventional synthesis chemistry, startingfrom corresponding commercially available compounds with an OH group inposition C3.

In particular, 3β-methoxy-PREG may be prepared from pregnenolone byaddition of p-toluenesulfonyl chloride in pyridine, stirring of themixture, addition of distilled water, cooling of the reaction to 0° C.,filtration and drying under vacuum to yield pregnenolone tosylate.Pregnenolone tosylate is then refluxed with methanol for 4 hours. Aftercooling and evaporation of the solvent, the crude reaction product iswashed in 10% sodium bicarbonate solution. After drying the organicphase over Na₂SO₄, it is evaporated dry under reduced pressure to yield3β-methoxy-PREG. A precise protocol is disclosed in Example 1 ofWO2004067010A1. 3β-methoxy-PREG is also commercially available, forinstance from Steraloids Inc (Newport, R.I., USA). Similar methods maybe used for preparation of other non-bioconvertible C₃-substitutedpregnenolone derivatives useful in the context of the present invention,starting from corresponding commercially available compounds with an OHgroup in position C3.

Administration of the Compounds

The above defined compounds or pharmaceutically acceptable saltsthereof, and in particular 3β-methoxy-PREG or pharmaceuticallyacceptable salts thereof, may be administered to any subject sufferingfrom a substance use disorder, in particular to any human subjectsuffering from a substance use disorder.

The above defined compounds or pharmaceutically acceptable saltsthereof, and in particular 3β-methoxy-PREG or pharmaceuticallyacceptable salts thereof, may be administered to a (preferably human)subject suffering from a substance use disorder via any suitableadministration route, including oral, intravenous, transdermal,subcutaneous, intranasal, topical, sublingual, and rectal routes.Preferred administrations routes include oral, subcutaneous, andintranasal routes.

Depending on the selected route of administration, those skilled in theart will know how to formulate the above defined compounds orpharmaceutically acceptable salts thereof in order to optimize in vivodelivery and bioavailability. In particular, the above defined compoundsor pharmaceutically acceptable salts thereof, and in particular3β-methoxy-PREG or pharmaceutically acceptable salts thereof, may beformulated with suitable pharmaceutically acceptable carriers,excipients, vehicles, preservatives, solubilizing agents, stabilizers,wetting agents, emulsifiers, sweeteners, dyes, flavoring, salts intendedto modify osmotic pressure, buffers, taste correctors, and antioxidants.These compounds are well-known to those skilled in the art. Details onthese chemicals can be found in the latest edition of Remington'sPharmaceutical Sciences (Maack Publishing Co., Easton, Pa.). Theselection of the optimal delivery formulation will be selected by thoseskilled in the art depending on the selected administration route.

Suitable unit dose administration formulations for oral administrationnotably include tablets, coated tablets, pills, capsules and softgelatin capsules, oral powders, granules, solutions and suspensions.

When a solid composition in tablet form is prepared, the principalactive ingredient may be mixed with a pharmaceutical vehicle, such asgelatin, starch, lactose, stearic acid or magnesium stearate, talc, gumarabic or analogues. The tablets may be coated with saccharose or othersuitable materials or even be treated so as to have a prolonged ordelayed activity and to release continuously a predetermined quantity ofthe active ingredient.

A capsule preparation may be obtained by mixing the active ingredientwith a thinner and pouring the mixture obtained into soft or hardcapsules, with excipients such as vegetable oils, waxes, fats,semi-solid or liquid polyols, etc.

A preparation in syrup or elixir form can contain the active ingredienttogether with a sweetener, an antiseptic, as well as an agent givingtaste and a suitable dye. Excipients may be used, such as water,polyols, saccharose, invert sugar, glucose, etc.

Powders or water-dispersible granules may contain the active ingredientin a mixture with dispersing agents, wetting agents, and suspendingagents, together with taste correctors and sweeteners.

For intravenous or intranasal administration, aqueous suspensions,isotonic saline solutions, or sterile, injectable solutions that containpharmacologically compatible dispersing agents and/or wetting agents maybe used. As an excipient, water, alcohols, polyols, glycerol, vegetableoils, etc., may be used.

For subcutaneous administration, any suitable pharmaceuticallyacceptable vehicle may be used. In particular, a pharmaceuticallyacceptable oil vehicle, such as sesame oil, may be used.

For topical administration, compositions may be presented in the form ofa gel, a paste, an ointment, a cream, a lotion, an aqueous oraqueous-alcohol liquid suspension, an oily solution, a dispersion of thelotion or serum type, an anhydrous or lipophilic gel, an emulsion with aliquid or semi-solid milk-type consistency obtained by dispersing afatty phase in an aqueous phase or vice versa, suspensions or emulsionsof a soft or semi-solid cream- or gel-type consistency, or alternativelymicroemulsions, microcapsules, microparticles, or vesicular dispersionsof the ionic and/or nonionic type. These compositions are preparedaccording to standard methods. Moreover, a surfactant can be included inthe composition in order to enable deeper penetration of the abovedefined compounds or pharmaceutically acceptable salts thereof, and inparticular 3β-methoxy-PREG or pharmaceutically acceptable salts thereof.An agent enabling an increased penetration may be selected, for example,from mineral oil, ethanol, triacetin, glycerin and propylene glycol;cohesion agents are selected, for example, from the group comprisingpolyisobutylene, polyvinyl acetate, polyvinyl alcohol, and thickeningagents.

For rectal administration, suppositories, which are prepared withbinders that melt at rectal temperatures, for example cocoa butter orsemi-solid or liquid polyols such as polyethylene glycols, waxes,natural or hydrogenated oils, fats, etc., can be used.

The above defined compounds or pharmaceutically acceptable saltsthereof, and in particular 3β-methoxy-PREG or pharmaceuticallyacceptable salts thereof, may be administered to a (preferably human)subject suffering from a substance use disorder at any dose suitable forobtaining a therapeutic effect. In particular, a suitable dose forhumans may be in the range of 50 to 2000 mg/day, in particular in therange of 50 to 1750 mg/day, in the range of 50 to 1500 mg/day, in therange of 50 to 1250 mg/day, in the range of 50 to 1000 mg/day, in therange of 50 to 750 mg/day, in the range of 50 to 500 mg/day, in therange of 100 to 2000 mg/day, in particular in the range of 100 to 1750mg/day, in the range of 100 to 1500 mg/day, in the range of 100 to 1250mg/day, in the range of 100 to 1000 mg/day, in the range of 100 to 750mg/day, in the range of 100 to 500 mg/day, in the range of 250 to 2000mg/day, in particular in the range of 250 to 1750 mg/day, in the rangeof 250 to 1500 mg/day, in the range of 250 to 1250 mg/day, in the rangeof 250 to 1000 mg/day, in the range of 250 to 750 mg/day, in the rangeof 250 to 500 mg/day, in the range of 500 to 2000 mg/day, in the rangeof 500 to 1750 mg/day, in the range of 500 to 1500 mg/day, in the rangeof 500 to 1250 mg/day, in the range of 500 to 1000 mg/day, or in therange of 500 to 750 mg/day.

The administered dose may vary depending on the subject age, bodysurface area or body weight, or on the administration route andassociated bioavailability. Such dose adaptation is well known to thoseskilled in the art.

SUDs to be Treated

The above defined compounds or pharmaceutically acceptable saltsthereof, and in particular 3β-methoxy-PREG or pharmaceuticallyacceptable salts thereof, may be used for treating any SUD. Indeed, mostSUDs share at least some common etiologies, alterations of neurologicalsignaling pathways and behaviors (Vanyukov M M, et al. Neurosci BiobehavRev. 2003 October; 27(6):507-15; Koob G F, Volkow N D.Neuropsychopharmacology. 2010 January; 35(1):217-38; Koob G F, Le MoalM. Philos Trans R Soc Lond B Biol Sci. 2008 Oct. 12; 363(1507):3113-23)and results obtained in models of alcohol use disorder may thusreasonably be extended to other substance use disorders. In particular,all SUD share:

-   -   Common liabilities (Vanyukov M M, et al. Neurosci Biobehav Rev.        2003 October; 27(6):507-15),    -   Common mechanisms of (Koob G F, Volkow N D.        Neuropsychopharmacology. 2010 January; 35(1):217-38; Koob G F,        Le Moal M. Philos Trans R Soc Lond B Biol Sci. 2008 Oct. 12;        363(1507):3113-23):        -   early neuroadaptation, with increased excitability of the            mesolimbic dopamine system reflected in long-term            potentiation dependent on changes in glutamate activity        -   common response of elevated adrenocorticotropic hormone,            corticosterone and amygdala CRF during acute withdrawal    -   Common behaviors of withdrawal/negative affect and        preoccupation/anticipation (Koob G F, Volkow N D.        Neuropsychopharmacology. 2010 January; 35(1):217-38; Koob G F,        Le Moal M. Philos Trans R Soc Lond B Biol Sci. 2008 Oct. 12;        363(1507):3113-23).

The above defined compounds or pharmaceutically acceptable saltsthereof, and in particular 3β-methoxy-PREG or pharmaceuticallyacceptable salts thereof, may thus be used for treating alcohol usedisorder; cannabis use disorder; hallucinogens (including phencyclidine,ketamine, and LSD) use disorders; opioids (including codeine, fentanyl,heroin, morphine, opium, methadone, oxycodone, and hydrocodone) usedisorders; sedative, hypnotic or anxiolytic medications (includingbarbiturates and benzodiazepines) use disorders; stimulants (includingnicotine, amphetamine, and methylphenidate) use disorders; and inhalants(such as glue, shoe polish, toluene, spray paints, gasoline, and lighterfluid) use disorders.

In a preferred embodiment, the above defined compounds orpharmaceutically acceptable salts thereof, and in particular3β-methoxy-PREG or pharmaceutically acceptable salts thereof, are foruse in the treatment of alcohol use disorder.

The following examples merely intend to illustrate the presentinvention.

EXAMPLES Example 1. Activity of 3β-methoxy-pregnenolone on progesteroneReceptor

The capacity of 3β-methoxy-pregnenolone to display progesteroneactivity, and thus to be considered as a progestin, was tested byassaying the activity of 3-methoxy-pregnenolone on progesteronereceptor.

Indeed, progesterone is an agonist of progesterone receptor, as are allprogestins. In contrast, compounds able to inhibit progesterone activityon its receptor are called progesterone receptor antagonists.

Methods

The main experimental setting used is the following: HEK293T cells weretransiently transfected, using calcium phosphate precipitationtechnology, with expression vectors pSG5hPR (which permits expression ofhuman progesterone receptor(PR)), pFC31-luc (contains the luciferasegene under the control of the MMTV promoter, which is in turn activatedby binding of a progestin to progesterone receptor) and pcbetagal (whichpermits expression of betagalactosidase), and cultured during 24 hourswith increasing amounts of various compositions:

-   -   1. Test of progesterone receptor agonist activity: transfected        cells were cultured with increasing amounts of progesterone or        3-methoxy-pregnenolone        -   With this setting, a compound with progesterone receptor            agonist activity permits a transactivation activity            resulting in the expression of luciferase (since the binding            of a progestin to PR results in activation of the MMTV            promoter, which directs the expression of luciferase).        -   In contrast, a compound without progesterone receptor            agonist activity does not permit a transactivation activity            and luciferase is not expressed (since PR is not activated            and thus does not activate the MMTV promoter);    -   2. Test of progesterone receptor agonist activity: transfected        cells were cultured with progesterone (1 nM) and increasing        amounts of RU486 (a well-known progesterone receptor antagonist)        or 3-methoxy-pregnenolone.        -   With this setting, a compound with progesterone receptor            antagonist activity competes with progesterone for the            occupation of progesterone receptor and results in a            progressive loss of transactivation activity when the amount            of this compound is increased compared to progesterone.

Results

The results obtained with experimental setting 1 (test of progesteronereceptor agonist activity) are displayed in FIG. 1.

FIG. 1 clearly shows that, contrary to progesterone, which permits atransactivation activity leading to the expression of luciferase,3-methoxy-pregnenolone does not permit such a transactivation activity,even at the highest tested concentrations, thus demonstrating that3β-methoxy-pregnenolone does not have progesterone receptor agonistactivity, and cannot thus be considered as a progestin.

The results obtained with experimental setting 2 (test of progesteronereceptor antagonist activity) are displayed in FIG. 2.

These results unambiguously show that even if 3β-methoxy-pregnenolonedoes not have the very high antagonist activity of RU486, it is a weakprogesterone receptor antagonist.

Example 2 3β-methoxy-PREG has no Androgenic, Estrogenic, Glucocorticoidand Mineral Corticoid Activity

Binding affinity of 3β-methoxy-PREG (MAP4343) for receptors of steroidhormones was evaluated using radioligand binding assays.

MAP4343 (10 μM) was ineffective (<25% inhibition) in displacing specificradioligands from the following binding sites: MineralocorticoidReceptor (MR), Androgen Receptor (AR), Estrogen Receptors (ERα and ERβ)and Glucorticoid Receptor (GR). The results are summarized below inTable 3 below.

TABLE 3 Affinity of MAP4343 (10 μM) for steroid hormones receptorsmeasured by radioligand binding assays. Biochemical assay results arepresented as the percent inhibition of specific binding (significantresponses: ≥ 50% inhibition). None of the results met significancecriteria at concentrations used. Target Ligand Source % inhibition* MR4.5 nM [³H] D-Aldosterone Wistar Rat kidney 25 AR 1.5 nM [³H] MiboleroneRat recombinant E. coli 18 ER□ 0.5 nM [³H] Estradiol Human recombinantSf9 −8 cells ER□ 0.5 nM [³H] Estradiol Human recombinant Sf9 16 cells GR3 nM [³H] Dexamethasone Human HeLa S3 cells 21 *Negative valuescorrespond to stimulation of binding or enzyme activity

Example 3 3β-methoxy-PREG has no Significant Affinity for Receptors ofthe Central Nervous System

MAP4343 has been screened for in vitro affinity to 80 different CNSneurotransmitters receptors using various validated binding assays.

The results show that MAP4343 has no significant affinity for any testedreceptor including the ones traditionally associated with side effectsor abuse liability. Results are summarized in following Table 4.

TABLE 4 In vitro affinity of MAP4343 (10 μM) for CNS neurotransmitterreceptors associated with side effects and/or abuse liability. Data arethe average of two individual assays for each receptor and are expressedas % inhibition of the control specific binding of the referencecompound. Results showing an inhibition higher than 50% are consideredto represen significant effects of the test compound. MAP4343 showed nosignificant effects on any of the tested receptor at the concentrationused. % Inhibition Receptor of control family Target Ligand Sourcespecific binding Muscarinic M₁ [³H] pirenzepine Human −3 (Cholinergic)recombinant (CHO cells) M₂ [³H] AF-DX 384 Human 20 recombinant (CHOcells) M₃ [³H] 4-DAMP Human 3 recombinant (CHO cells) M₄ [³H] 4-DAMPHuman 20 recombinant (CHO cells) M₅ [³H] 4-DAMP Human 12 recombinant(CHO cells) Histaminergic H₁ [³H] pyrilamine Human 9 recombinant (HEK-293 cells) H₂ [¹²⁵I] APT Human −21 recombinant (CHO cells) Noradrenergicα₁ [³H] prazosin rat cerebral cortex 4 α₂ [³H] RX 821002 rat cerebralcortex 7 β₁ [³H] (-) CGP 12177 Human 1 recombinant (HEK- 293 cells) β₂[³H] (-) CGP 12178 Human −4 recombinant (CHO cells) Transporter [³H]nisoxetine Human 3 recombinant (CHO cells) Serotoninergic 5-HT_(1A) [³H]8-OH-DPAT Human 2 recombinant (HEK- 293 cells) 5-HT_(1B) [¹²⁵I] CYP +rat cerebral cortex 4 (-) propranolol 5-HT_(2A) [³H] ketanserin Human 1recombinant (HEK- 293 cells) 5-HT_(2B) [¹²⁵I] (±) DOI Human −4recombinant (CHO cells) 5-HT_(2C) [³H] mesulergine Human 7 recombinant(CHO cells) 5-HT₃ [³H] BRL 43694 Human 10 recombinant (CHO cells)5-HT_(5A) [³H] LSD Human −5 recombinant (CHO cells) 5-HT₆ [³H] LSD Human12 recombinant (CHO cells) 5-HT₇ [³H] LSD Human −11 recombinant (CHOcells) Transporter [³H] imipramine Human 3 recombinant (CHO cells)Dopaminergic D₁ [³H] SCH 23390 Human 2 recombinant (CHO cells) D_(2S)[³H] spiperone Human 6 recombinant (HEK- 293 cells) D₃ [³H] spiperoneHuman 8 recombinant (CHO cells) D_(4.4) [³H] spiperone Human 6recombinant (CHO cells) D₅ [³H] SCH 23390 Human −7 recombinant (GH4cells) Transporter [³H] BTCP Human recombinant (CHO cells) GABA(non-selective) [³H] GABA rat cerebral cortex 2 NMDA PCP site [³H] TCPrat cerebral cortex −10 Cannabinoid CB₁ [³H] CP55940 Human 12recombinant (CHO cells) Oppioid δ₂ [³H] DADLE Human −3 recombinant (CHOcells) κ [³H] U 69593 rat recombinant 19 (CHO cells) μ [³H] DAMGO Human0 recombinant (HEK- 293 cells)

Example 4 Effect of Chronic 3β-methoxy-PREG on AlcoholSelf-Administration in Ethanol Dependent and Non-Dependent Animals

Alcohol self-administration in ethanol dependent and non-dependentanimals is a well-known and well-characterized animal model for analysisof alcoholism behaviors (Roberts et al. 1999, 2000; Rimondini et al.2002; O'Dell et al. 2004; Richardson et al. 2008; Gilpin et al. 2009).Numerous studies have demonstrated that this model has robust predictivevalidity for alcohol addiction (Heilig and Koob 2007; Koob et al. 2009)This model has been used to test the effect of chronic 3β-methoxy-PREGadministration in a model of alcoholism.

Materials and Methods Subjects

Adult male Wistar rats (Charles River, Raleigh, N.C.), weighing 225-275g at the beginning of the experiments, were housed in groups of 2-3 percage in a temperature-controlled (22° C.) vivarium on a 12 h/12 hlight/dark cycle (lights on at 8:00 PM) with ad libitum access to foodand water. All behavioral tests were conducted during the dark phase ofthe light/dark cycle. All procedures adhered to the National Institutesof Health Guide for the Care and Use of Laboratory Animals and wereapproved by the Institutional Animal Care and Use Committee of TheScripps Research Institute.

Operant Self-Administration

Self-administration sessions were conducted in standard operantconditioning chambers (Med Associates, St. Albans, Vt.). Animals werefirst trained to self-administer 10% (w/v) ethanol and water solutionsuntil a stable response was maintained. The rats were subjected to anovernight session in the operant chambers with access to one lever(right lever) that delivered water (FR1). Food was available ad libitumduring this training. After 1 day off, the rats were subjected to a 2 hsession (FR1) for 1 day and a 1 h session (FR1) the next day, with onelever delivering alcohol (right lever). All of the subsequent sessionslasted 30 min, and two levers were available (left lever: water; rightlever: alcohol) until stable levels of intake were reached. Uponcompletion of this procedure, the animals were allowed toself-administer a 10% (w/v) alcohol solution and water on an FR1schedule of reinforcement (i.e., each operant response was reinforcedwith 0.1 ml of the solution).

Alcohol Vapor Chambers

Once a stable baseline of alcohol self-administration was reached, therats were made dependent by chronic, intermittent exposure to alcoholvapors. They underwent cycles of 14 h on (blood alcohol levels duringvapor exposure ranged between 150 and 250 mg %) and 10 h off, duringwhich behavioral testing for acute withdrawal occurred (i.e., 6-8 hafter vapor was turned off when brain and blood alcohol levels arenegligible). In this model, rats exhibit somatic withdrawal signs andnegative emotional symptoms reflected by anxiety-like responses andelevated brain reward thresholds. Nondependent rats were not exposed toalcohol vapor.

Operant Self-Administration During Alcohol Vapor Exposure

Behavioral testing occurred 3 times per week. The rats were tested foralcohol (and water) self-administration on an FR1 schedule ofreinforcement for 30 min sessions. Operant self-administration on an FR1schedule requires minimal effort by the animal to obtain thereinforcement and herein was considered a measure of intake.

Drugs

Alcohol drinking solution 10% (w/v) was prepared by dilution of ethanol95% (w/v) in water. 3β-methoxy-PREG (referred to as “MAP4343” inExample 1) was dissolved in sesame oil and injected sub-cutaneously atthe dose of 10 mg/kg 24 hours before each test session.

Blood Samples

Blood samples were obtained before and after completion of the treatmentwith MAP4343 using retro-orbital sampling. Blood, serum and plasma werecollected and analyzed using standard procedures to evaluate blood countpanel, blood urea nitrogen, cholesterol, creatinine, T3, T4 and proteinelectrophoresis.

Statistical Analysis

Data were analyzed by appropriate mixed factorial ANOVA, followed NewmanKeuls post hoc tests

Results Behavioral Results

At the end of the self-administration training the baseline of ethanolresponses was 49.2±9.1 for the ethanol dependent animals and 20.3±5.9for the non-dependent rats (see FIG. 3).

At this point the treatment started and dependent and non-dependentanimals were divided into 2 groups in order to be injected with MAP4343or its vehicle 24 hours before the test sessions. The total experimentlasted 18 days with 9 injections and 9 test sessions (see FIG. 3).

Mixed factorial ANOVA with dependence (dependent/non-dependent) andtreatment (veh/MAP4343) as between factors and the time (number of testsessions) as within factor showed a significant effect of the dependence[F(1,15)=39.01; p<0.001] and of the dependence*treatment interaction[F(1,15)=4.50; p<0.05] (see FIG. 3).

Newman Keuls post hoc test showed that the treatment with MAP4343 wasable to significantly reduce operant responding for alcohol selectivelyin the dependent animals (p<0.05) starting from the test session 8(after the injection 7) and lasting for the rest of the treatment.

Blood Results

Mixed factorial ANOVA with dependence (dependent/non-dependent) andtreatment (veh/MAP4343) as between factors and the time (pre/post) aswithin factor showed no significant effects of dependence or treatmenton any of the blood parameters investigated (See FIGS. 4 to 17).

Conclusions

Map4343 produced significant reduction of excessive alcohol drinkingspecifically in alcohol dependent rats and not in non-dependent rats.Efficacy of the treatment was apparent after ˜10 days of treatment andwas maintained during the entire duration of the treatment. No effect oftreatment was observed on any of the blood parameters measured. Theseresults suggest that MAP4343, and other compounds targetingmicrotubules, may represent a new therapeutic strategy to reduceexcessive alcohol drinking. The lack of effect of MAP4343 on any of theblood parameters measured suggests that MAP4343 treatment does not havemajor adverse toxic effect.

Example 5 Other Molecules According to the Invention

The indices of binding and activity are expressed as a percent ofpregnenolone (PREG).

Binding (affinity) is measured by the displacement of PREG-³H.

Activity is measured by the increase in optical density at 345 nm of amixture of purified tubulin and MAP2, incubated at 37° C. in thepresence of GTP.

Stimulation of neuritic sprouting is conducted on PC12 cellsdifferentiated in the presence of NGF (10 ng/ml) and the steroid beingtested (30 μM) for 3 days. For each condition, the average length of thelongest 200 neurites in each cell is measured simultaneously for 3cultures.

The results are represented in Table 5 below by one, two or threecrosses (+) according to whether stimulation is lower than, equal to, orhigher than that produced by PREG.

TABLE 5 Indices of binding and activity of other molecules, expressed asa percent of PREG Neuritic Steroid Affinity Activity sproutingPregnenolone (PREG) 100 100 ++ 3B-methoxy-pregna-5-ene-20-one(3- 100 100+++ methoxy-PREG) 3B-methoxy-pregna-5-ene-20-one-17a- 53 113 +++dichloromethyl 3B-methoxy-5a-pregnane-20-one 87 10 +++3B-methoxy-5a-pregnane-20B-ol 65 65 ++3B-methoxy-pregna-5,14-diene-20-one 102 50 +

These results show the effectiveness of other molecules derived frompregnenolone to stimulate the polymerization of microtubules induced byMAP2 and to stimulate neuritic sprouting. It may thus be expected thatthese derivatives will at least maintain the activity of3β-methoxy-pregna-5-ene-20-one (3β-methoxy-PREG).

BIBLIOGRAPHIC REFERENCES

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1. A method for treating or preventing relapse of a substance usedisorder in a subject in need thereof, comprising administering to saidsubject a therapeutically effective amount of a compound of formula (I):

wherein: each of

independently represents a single or a double bond; R₁ represents aC₁-C₄ alkyl; R₂ represents —CO—; —CH(OH)— or —CH(O—COCH₃)—; and R₃represents H or CHCl₂ and R₄ represents H or CH₃, or R₃ and R₄ togetherrepresent

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein said compound is of formula (II):

wherein:

represents a single or a double bond; R₁ represents a C₁-C₄ alkyl; R₂represents —CO— or —CH(OH)—; and R₃ represents H or CHCl₂.
 3. The methodof claim 2, wherein R₁ is CH₃.
 4. The method of claim 2, wherein

is a double bond.
 5. The method of claim 2, wherein R₂ is —CO—.
 6. Themethod of claim 2, wherein R₃ represents H.
 7. The method of claim 1,wherein said compound is selected from the following compounds:

and pharmaceutically acceptable salts thereof.
 8. The method of claim 7,wherein said compound is 3-methoxy-pregna-5-ene-20-one of formula:

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 1,wherein said compound is selected from the following compounds:

and pharmaceutically acceptable salts thereof.
 10. The method of claim9, wherein said compound is 3β-methoxy-pregna-5-ene-20-one of formula:

or a pharmaceutically acceptable salt thereof.
 11. The method of claim1, wherein said substance use disorder is selected from alcohol usedisorder; cannabis use disorder; hallucinogens (including phencyclidine,ketamine, and LSD) use disorders; opioids (including codeine, fentanyl,heroin, morphine, opium, methadone, oxycodone, and hydrocodone) usedisorders; sedative, hypnotic or anxiolytic medications (includingbarbiturates and benzodiazepines) use disorders; stimulants (includingnicotine, amphetamine, and methylphenidate) use disorders; and inhalants(such as glue, shoe polish, toluene, spray paints, gasoline, and lighterfluid) use disorders.
 12. The method of claim 11, wherein said substanceuse disorder is alcohol use disorder (AUD).
 13. The method of claim 1,wherein said compound or pharmaceutically acceptable salt thereof isadministered via oral, intravenous, transdermal, subcutaneous,intranasal, topical, sublingual, or rectal route.
 14. The method ofclaim 1, wherein said compound or pharmaceutically acceptable saltthereof is administered at a dose of 50 to 2000 mg/day.
 15. The methodof claim 1, wherein said compound or pharmaceutically acceptable saltthereof is part of a pharmaceutical composition further comprising atleast one pharmaceutically acceptable excipient.
 16. A method fortreating or preventing relapse of an alcohol use disorder (AUD) in asubject in need thereof, comprising administering to said patient atherapeutically efficient amount of compound3β-methoxy-pregna-5-ene-20-one of formula:

or a pharmaceutically acceptable salt thereof.
 17. The method of claim16, wherein said compound or pharmaceutically acceptable salt thereof isadministered via oral, intravenous, transdermal, subcutaneous,intranasal, topical, sublingual, or rectal route.
 18. The method ofclaim 16, wherein said compound or pharmaceutically acceptable saltthereof is administered at a dose of 50 to 2000 mg/day.
 19. The methodof claim 16, wherein said compound or pharmaceutically acceptable saltthereof is part of a pharmaceutical composition further comprising atleast one pharmaceutically acceptable excipient.
 20. The method of claim11, wherein said compound is 3β-methoxy-pregna-5-ene-20-one of formula:

or a pharmaceutically acceptable salt thereof.